2,6-dihalo-5-alkoxy-4-substituted-pyrimidines, pyrimidine-carbaldehydes, and methods of formation and use

ABSTRACT

2,6-Dihalo-5-alkoxy-4-substituted-pyrimidines, 2,6-dihalo-5-alkoxy-4-pyrimdine carbaldehydes, and derivatives of each are useful intermediates in forming potent herbicides that demonstrate a broad spectrum of weed control. These compounds are disclosed, as are methods of forming and using these compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/582,156, filed Dec. 30, 2011, the disclosure ofwhich is hereby incorporated herein in its entirety by this reference.

TECHNICAL FIELD

Embodiments of the present disclosure relate to2,6-dihalo-5-alkoxy-4-substituted pyrimidines. Embodiments of thepresent disclosure also related to 2,6-dihalo-5-alkoxy-4-pyrimidinecarbaldehydes. Embodiments of the present disclosure further relate tomethods of foaming 2,6-dihalo-5-alkoxy-4-substituted-pyrimidines and2,6-dihalo-5-alkoxy-4-pyrimidine carbaldehydes and methods of using thesame.

BACKGROUND

2,6-dihalo-5-alkoxy-pyrimidine-4-carboxylic acids and esters are usefulintermediates for the preparation of pharmaceutical and agriculturalchemicals, such as herbicides. Conventional methods to form thesecompounds may be laborious, low yielding, and not easily scalable.

BRIEF SUMMARY

An embodiment of the present disclosure includes compounds of Formula I:

wherein

X₁ represents a halogen;

R₁ represents a hydrocarbon chain; and

Q represents a C₁-C₂ alkoxy.

In particular embodiments, compounds of Formula I independently includethose in which X₁ represents chlorine, wherein Q represents methoxy, andwherein R₁ represents a hydrocarbon chain oxidizable to an acid, forexample, without limitation, an alkyl, vinylic, aryl, alkenyl, orfuranyl, with R₁ representing vinylic being most preferred.

Another embodiment of the present disclosure includes compounds ofFormula II:

wherein

X₁ represents a halogen; and

Q represents a C₁-C₂ alkoxy.

Representative compounds of Formula II independently include those inwhich X₁ represents chlorine and wherein Q represents methoxy.

Another embodiment of the present disclosure includes a method offorming a compound of Formula II, i.e., a2,6-dihalo-5-alkoxy-pyrimidine-4-carbaldehyde, by reacting a compound ofFormula I, i.e., a 2,6-dihalo-5-alkoxy-4-substituted pyrimidine with anoxidant.

Yet another embodiment of the present disclosure includes a method offorming a compound of Formula I, i.e., a2,6-dihalo-5-alkoxy-4-substituted pyrimidine, comprising reacting a2,6-dihalo-5-alkoxy pyrimidine with an organometallic reagent to form a2,6-dihalo-5-alkoxy-4-substituted-3-(metal-halo or metal) pyrimidine andoxidizing the 2,6-dihalo-5-alkoxy-4-substituted-3-(metal-halo or metal)pyrimidine to form the 2,6-dihalo-5-alkoxy-4-substituted pyrimidine.

Another particular embodiment of the present disclosure includes amethod of using a 2,6-dihalo-5-alkoxy-4-substituted pyrimidine to forman alkyl 6-amino-2-halo-5-alkoxy-pyrimidine-4-carboxylate. The2,6-dihalo-5-alkoxy-4-substituted pyrimidine comprises a pyrimidine ringcomprising a 4 position and a 6 position. The pyrimidine ring comprisesa hydrocarbon chain at the 4 position. The pyrimidine ring comprises ahalogen at the 6 position. The method of using the2,6-dihalo-5-alkoxy-4-substituted pyrimidine comprises contacting thehydrocarbon chain at the 4 position with an oxidant to form a carbonylgroup at the 4 position. The carbonyl group is contacted at the 4position with bromine in an alcohol to form a carboalkoxy group at the 4position. The halogen is contacted at the 6 position with an amine toform an amino group at the 6 position.

DETAILED DESCRIPTION

As used herein, the term “alkyl” refers to an acyclic, saturated,branched or unbranched, substituent consisting of carbon and hydrogen,for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl,isobutyl, tert-butyl, pentyl, 2-methylbutyl, 1,1-dimethylpropyl, hexyl,heptyl, octyl, nonyl, and decyl.

As used herein, the term “alkoxy” refers to an alkyl group bonded to anoxygen, for example, methoxy and ethoxy.

As used herein, the term “halo” refers to fluoro, chloro, bromo, andiodo.

As used herein, the term “halogen” refers to fluorine, chlorine,bromine, and iodine.

As used herein, the term Grignard reagent refers to an organomagnesiumhalide.

Compounds of Formula I, as follows, are useful intermediates in formingcompounds used in preparing pharmaceutical and agricultural chemicals,such as herbicides:

wherein

X₁ represents a halogen;

R₁ represents a hydrocarbon chain; and

Q represents a C₁-C₂ alkoxy.

Such 2,6-dihalo-5-alkoxy-4-substituted pyrimidines may include apyrimidine ring having halogens at the 2 and 6 positions, a C₁-C₂ alkoxygroup at the 5 position, and a hydrocarbon chain at the 4 position. Thehalogens at the 2 and 6 positions may be chlorine, such that thecompound may be a 2,6-dichloro-5-alkoxy-4-substituted pyrimidine. Thealkoxy group at the 5 position may be methoxy, such that the compoundmay be a 2,6-dihalo-5-methoxy-4-substituted pyrimidine. The hydrocarbonchain at the 4 position is a hydrocarbon group oxidizable to an acid.The chain may include, for example and without limitation, an alkyl,vinylic, aryl, alkenyl, or furanyl group. In some embodiments, thehydrocarbon chain at the 4 position may be a vinylic group, such thatthe compound is a 2,6-dihalo-5-alkoxy-4-vinylic pyrimidine. The compoundof Formula I may be 2,6-dichloro-5-methoxy-4-vinylic pyrimidine.

Compounds of Formula II, as follows, are also useful intermediates informing compounds used in preparing pharmaceutical and agriculturalchemicals, such as herbicides:

wherein

X₁ represents a halogen; and

Q represents a C₁-C₂ alkoxy.

Such 2,6-dihalo-5-alkoxy-pyrimidine-4-carbaldehydes can include apyrimidine ring having halogens at the 2 and 6 positions, a C₁-C₂ alkoxygroup at the 5 position, and a carbonyl group at the 4 position. Thehalogens at the 2 and 6 positions may be chlorine, such that thecompound may be a 2,6-dichloro-5-alkoxy-pyrimdine-4-carbaldehyde. Thealkoxy group at the 5 position may be methoxy, such that the compoundmay be a 2,6-dihalo-5-methoxy-pyrimidine-4-carbaldehyde. The compound ofFormula II may be 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde.

One embodiment of forming a compound of Formula II using a compound ofFormula I is shown in Scheme 1, as follows:

As shown in Scheme 1, a compound of Formula II, i.e., a2,6-dihalo-5-alkoxy-pyrimidine-4-carbaldehyde, can be prepared byoxidizing a compound of Formula I, i.e., a2,6-dihalo-5-alkoxy-4-substituted pyrimidine. The method of Scheme 1includes reacting a compound of Formula I with an oxidant to form acompound of Formula II.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; andR₁ represents a hydrocarbon chain. The oxidant may be ozone (O₃).

The method of Scheme 1 includes contacting the hydrocarbon chain at the4 position of the pyrimidine ring of the compound of Formula I with anoxidant to form a carbonyl group at the 4 position of the pyrimidinering in the resulting compound of Formula II. Thus, the compound ofFormula II may be the carbaldehyde derivative of the compound of FormulaI.

The method of Scheme 1 may include introducing the oxidant with asolvent. The solvent may be a halogenated solvent, e.g., dichloromethane(DCM). The solvent may be methanol.

The method of Scheme 1 is illustrated in each of Examples 6 and 7.

One embodiment of forming a compound of Formula I is shown in Scheme 2,as follows:

As shown in Scheme 2, a compound of Formula I, i.e., a2,6-dihalo-5-alkoxy-4-substituted pyrimidine, can be prepared using acompound of Formula III, i.e., a 2,6-dihalo-5-alkoxy pyrimidine. Themethod of Scheme 2 includes reacting a compound of Formula III with anorganometallic reagent of Formula IV to form an intermediate of FormulaV and reacting the intermediate of Formula V with an oxidant to form acompound of Formula I.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₁represents a hydrocarbon chain that is oxidizable to an acid, e.g., analkyl, vinylic, or aryl. M₁ represents magnesium; and X₂ representsbromine, iodine, or chlorine; or M₁-X₂ and M₁X₂ represent, together,lithium. “Oxidant₁” may be an appropriate oxidant, e.g., an organicoxidant such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ); aninorganic oxidant such as manganese dioxide (MnO₂); a halogen-basedoxidant; or atmospheric oxygen in a metal-catalyzed oxidation reaction.

The organometallic reagent of Formula IV may be a Grignard reagent, suchthat M₁ represents magnesium and X₁ represents a halogen. The Grignardreagent may be a magnesium bromide reagent. For example, withoutlimitation, the Grignard reagent may be vinyl magnesium bromide. Use ofan organo-magnesium bromide Grignard reagent may be conducive forcarrying out the method of Scheme 2 at temperatures near roomtemperature or, alternatively, at temperatures near or greater than 0°C. The organometallic reagent of Formula IV may alternatively be anorganolithium reagent such that M₁ represents lithium. Use of anorganolithium reagent may further include carrying out Scheme 2 attemperatures at or below −40° C.

Reacting a compound of Formula III with the organometallic reagent ofFormula IV may form an intermediate compound of Formula V, i.e., ananionic 2,6-dihalo-5-alkoxy-4-substituted-3-(metal-halo or metal)pyrimidine. In embodiments in which the organometallic reagent ofFormula IV is a Grignard reagent, the resulting intermediate compound ofFormula V is an anionic 2,6-dihalo-5-alkoxy-4-substituted-3-metal-halopyrimidine. In embodiments in which the organometallic reagent ofFormula IV is an organolithium reagent, the resulting intermediatecompound of Formula V is an anionic2,6-dihalo-5-alkoxy-4-substituted-3-metal pyrimidine.

The organometallic reagent of Formula IV may be provided with a solventappropriate for an organometallic reagent reaction, such astetrahydrofuran (THF); 1,4-dioxane; diethyl ether; dimethyl oxide; ordimethoxyethane.

Reacting the compound of Formula III with the organometallic halidereagent of Formula IV may form a hydrocarbon chain at the 4 position ofthe pyrimidine ring and may form a metal halide or metal group, i.e., ametal (halide) group, at the 3 position of the pyrimidine ring. Reactingthe intermediate compound of Formula V with an appropriate oxidant mayform a compound of Formula I, with the hydrocarbon chain at the 4position of the pyrimidine ring.

The method of Scheme 2 may further include introducing a proton sourceto the reaction. The proton source may be wet acetone, acetic acid, or asimilarly-functioning compound.

The method of Scheme 2 may be accomplished without isolation of theintermediate compound of Formula V. Therefore, the oxidation to form acompound of Formula I may be accomplished in situ. The prepared compoundof Formula I may or may not be isolated before use thereof.

The method of Scheme 2 is illustrated in each of Examples 1 through 5.

One embodiment of using a compound of Formula II to form a compound ofFormula VII is shown in Scheme 3, as follows:

As shown in Scheme 3, a compound of Formula VII, i.e., an alkyl2,6-dihalo-5-alkoxy-pyrimidine-4-carboxylate, can be prepared using acompound of Formula II, i.e., a2,6-dihalo-5-alkoxy-pyrimidine-4-carbaldehyde.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; andR₂ represents an alkyl. R₂ may represent methyl.

The method of Scheme 3 includes contacting the carbonyl group at the 4position of the pyrimidine ring of the compound of Formula II withbromine in an alcohol of Formula VI to form a carboalkoxy group at the 4position of the pyrimidine ring in the resulting compound of FormulaVII.

Accordingly, the method of Scheme 3 provides a method of using acompound of Formula II to prepare a compound of Formula VII. Also, thecombined methods of Schemes 1 and 3 provide a method of using a compoundof Formula I to prepare a compound of Formula VII. Also, the combinedmethods of Schemes 1, 2, and 3 provide a method of using a compound ofFormula III to prepare a compound of Formula VII. Formed compounds mayor may not be isolated between combined schemes.

The method of Scheme 3 is illustrated in each of Examples 8 and 9.

One embodiment of using a compound of Formula VII to form a compound ofFormula IX is shown in Scheme 4, as follows:

As shown in Scheme 4, a compound of Formula IX, i.e., an alkyl6-amino-2-halo-5-alkoxy-pyrimidine-4-carboxylate, can be prepared usinga compound of Formula VII, i.e., an alkyl2,6-dihalo-5-alkoxy-pyrimidine-4-carboxylate. The method of Scheme 4includes reacting the compound of Formula VII with an amine of FormulaVIII (or salts thereof) to form the compound of Formula IX.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₂represents an alkyl; and R₃ and R₄ independently represent H, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxyl, C₁-C₆ alkoxy, amino,C₁-C₆ acyl, C₁-C₆ carboalkoxy, C₁-C₆ alkylcarbamyl, C₁-C₆ alkylsulfonyl,C₁-C₆ trialkylsilyl, or C₁-C₆ dialkyl phosphonyl, or R₃ and R₄ takentogether with N represent a 5- or 6-membered saturated ring.

The method of Scheme 4 may further include use of a solvent. Forexample, without limitation, a solvent used in the method may includedimethyl sulfoxide.

The method of Scheme 4 includes contacting the halogen at the 6 positionof the pyrimidine ring of the compound of Formula VII with an amine ofFormula VIII to form an amino group at the 6 position of the pyrimidinering in the resulting compound of Formula IX.

Accordingly, the method of Scheme 4 provides a method of using acompound of Formula VII to prepare a compound of Formula IX. Also, thecombined methods of Schemes 3 and 4 provide a method of using a compoundof Formula II to prepare a compound of Formula IX. Also, the combinedmethods of Schemes 1, 3, and 4 provides a method of using a compound ofFormula I to prepare a compound of Formula IX. Also, the combinedmethods of Schemes 1 through 4 provides a method of using a compound ofFormula III to prepare a compound of Formula IX. Formed compounds may ormay not be isolated between combined schemes.

The method of Scheme 4 is illustrated in each of Examples 10 and 11.Other embodiments and examples of this method are described in U.S. Pat.No. 7,642,220 to Epp et al. (“Scheme 2” therein), the disclosure ofwhich is incorporated by reference herein.

One embodiment of using a compound of Formula IX to form a compound ofFormula XI is shown in Scheme 5, as follows:

As shown in Scheme 5, a compound of Formula XI, i.e., an alkyl2-(substituted phenyl)-6-amino-5-alkoxy-pyrimidine-4-carboxylate, can beprepared using a compound of Formula IX, i.e., an alkyl6-amino-2-halo-5-alkoxy-pyrimidine-4-carboxylate. The method of Scheme 5includes reacting the compound of Formula IX with an organometalliccompound of Formula X to form the compound of Formula XI. The method mayinclude an inert solvent.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₂represents an alkyl; and R₃ and R₄ independently represent H, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxyl, C₁-C₆ alkoxy, amino,C₁-C₆ acyl, C₁-C₆ carboalkoxy, C₁-C₆ alkylcarbamyl, C₁-C₆ alkylsulfonyl,C₁-C₆ trialkylsilyl, or C₁-C₆ dialkyl phosphonyl, or R₃ and R₄ takentogether with N represent a 5- or 6-membered saturated ring.

Ar represents a phenyl group substituted with one or more substituentsselected from halogen, nitro, cyano, formyl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₂-C₄ alkoxyalkyl, C₂-C₆ alkylcarbonyl,C₁-C₆ alkythio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₄alkenyloxy, C₂-C₄ alkynloxy, C₂-C₄ alkenylthio, C₂-C₄ alkynylthio, C₁-C₆haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl, C₁-C₆ haloalkoxy, C₂-C₄haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkythio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₄haloalkenyloxy, C₂-C₄ haloalkynyloxy, C₂-C₄ haloalkenylthio, C₂-C₄haloalkynylthio, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂O—, —OCH2CH2O—, C(O)OR₆,—C(O)NR₅R₆, —CR₅NOR₆, —NR₅R₆, —NR₅OR₆, —NR₅SO₂R₆, —NR₅C(O)R₆,—NR₅C(O)OR₆, —NR₅C(O)NR₅R₆ or —NCR₅NR₅R₆. R₅ represents H, C₁-C₄ alkylor C₁-C₄ haloalkyl. R₆ represents C₁-C₄ alkyl or C₁-C₄ haloalkyl.

M₂ can be tri-(C₁-C₄ alkyl)tin or B(OR₇)(OR₈) where R₇ and R₈ are,independently of one another, hydrogen, C₁-C₆ alkyl, or when takentogether form an ethylene or propylene group. “Catalyst” can be atransition metal catalyst, in particular a palladium catalyst such asbis(triphenylphosphine)palladium(II) dichloride.

The method of Scheme 5 includes replacing the halogen at the 2 positionof the pyrimidine ring of the compound of Formula IX with thesubstituted phenyl group at the 2 position of the pyrimidine ring in theresulting compound of Formula XI.

Accordingly, the method of Scheme 5 provides a method of using acompound of Formula IX to prepare a compound of Formula XI. Also, thecombined methods of Schemes 4 and 5 provide a method of using a compoundof Formula VII to prepare a compound of Formula XI. Also, the combinedmethods of Schemes 3, 4, and 5 provide a method of using a compound ofFormula II to prepare a compound of Formula XI. Also, the combinedmethods of Schemes 1, 3, 4, and 5 provide a method of using a compoundof Formula I to prepare a compound of Formula XI. Also, the combinedmethods of Schemes 1 through 5 provide a method of using a compound ofFormula III to prepare a compound of Formula XI. Formed compounds may ormay not be isolated between combined schemes.

The method of Scheme 5 is illustrated in examples described in U.S. Pat.No. 7,642,220 to Epp et al. (“Scheme 1” therein), the disclosure ofwhich is herein incorporated by reference.

Compounds of Formula XI and their corresponding carboxylic acids and/orsalts are known to be superior herbicides with a broad spectrum of weedcontrol against broadleaf weeds as well as grass and sedge weeds andwith excellent crop selectivity at low use rates. These compoundsfurther possess excellent toxicological or environmental profiles. Thecarboxylic acids of Formula XI are believed to be the compounds thatactually kill or control undesirable vegetation. Analogs of thesecompounds in which the acid group or the carboalkoxy group of thepyrimidine carboxylic acid or ester is derivatized to form a relatedsubstituent that can be transformed within plants or the environment toan acid group or ester possess essentially the same herbicidal effect.Therefore, utilizing methods of Schemes 1 through 5, individually or incombination, one may use pyrimidine compounds of Formulas I, II, III, V,VII, and/or IX to prepare an herbicidal compound with Formula XI and/oragriculturally acceptable derivatives thereof. An “agriculturallyacceptable derivative,” when used to describe the carboxylate orcarboxylic acid functionality at the 4 position, is defined as any salt,ester, carboxylic acid, acylhydrazide, imidate, thioimidate, amidine,amide, orthoester, acylcyanide, acyl halide, thioester, thionoester,dithiolester, nitrile or any other ester or acid derivative well knownin the art that (a) does not substantially affect the herbicidalactivity of the active ingredient, i.e., the 2-(substitutedphenyl)-6-amino-5-alkoxy-4-pyrimidine-carboxylic acid, and (b) is or canbe hydrolyzed, oxidized, or metabolized in plants or soil to the2-(substituted phenyl)-6-amino-5-alkoxy-4-pyrimidine carboxylic acid orester that, depending upon the pH, is in the dissociated or theundissociated form. The preferred agriculturally acceptable derivativesof the carboxylic acid are agriculturally acceptable salts, acids,esters and amides.

Another embodiment of using a compound of Formula I is shown in Scheme6, as follows:

As shown in Scheme 6, a compound of Formula XII, i.e., a2,6-dihalo-5-alkoxy-pyrimidine-4-carboxylic acid, can be prepared usinga compound of Formula I, i.e., a 2,6-dihalo-5-alkoxy-4-substitutedpyrimidine.

In this case X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; andR₁ represents a hydrocarbon chain. The hydrocarbon chain is oxidizableto an acid. For example, without limitation, the hydrocarbon chain maybe an alkyl, vinylic, aryl, alkenyl, or furanyl. “Oxidant₂” representsan appropriate oxidant, e.g., potassium permanganate or oxygen in acatalyzed oxidation.

The method of Scheme 6 includes contacting the hydrocarbon chain at the4 position of the pyrimidine ring of the compound of Formula I with anoxidant to form a carboxyl group at the 4 position of the pyrimidinering of the resulting compound of Formula XII.

Accordingly, the method of Scheme 6 provides a method of using acompound of Formula I to prepare a compound of Formula XII. Also, thecombined methods of Schemes 2 and 6 provide a method of using a compoundof Formula III to prepare a compound of Formula XII. Formed compoundsmay or may not be isolated between combined schemes.

Still another embodiment of using a compound of Formula I is shown inScheme 7, as follows:

As shown in Scheme 7, a compound of Formula XIII, i.e., a6-amino-2-halo-5-alkoxy-4-substituted pyrimidine, can be prepared usinga compound of Formula I, i.e., a 2,6-dihalo-5-alkoxy-4-substitutedpyrimidine. The method of Scheme 7 includes reacting the compound ofFormula I with an amine of Formula VIII to faun the compound of FormulaXIII.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₁represents a hydrocarbon chain; and R₃ and R₄ independently represent H,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxyl, C₁-C₆ alkoxy,amino, C₁-C₆ acyl, C₁-C₆ carboalkoxy, C₁-C₆ alkylcarbamyl, C₁-C₆alkylsulfonyl, C₁-C₆ trialkylsilyl, or C₁-C₆ dialkyl phosphonyl, or R₃and R₄ taken together with N represent a 5- or 6-membered saturatedring.

The method of Scheme 7 may further include use of a solvent. Forexample, without limitation, a solvent used in the method may includedimethyl sulfoxide.

The method of Scheme 7 includes contacting the halogen at the 6 positionof the pyrimidine ring of the compound of Formula I with the amine ofFormula VIII to form an amino group at the 6 position of the pyrimidinering in the resulting compound of Formula XIII.

Accordingly, the method of Scheme 7 provides a method of using acompound of Formula I to prepare a compound of Formula XIII. Also, thecombined methods of Schemes 2 and 7 provide a method of using a compoundof Formula III to prepare a compound of Formula XIII. Formed compoundsmay or may not be isolated between combined schemes.

The method of Scheme 7 is illustrated in Example 12.

One embodiment of using a compound of Formula XIII to form a compound ofFormula XIV is shown in Scheme 8, as follows:

As shown in Scheme 8, a compound of Formula XIV, i.e., a6-amino-2-halo-5-alkoxy-pyrimidine-4-carbaldehyde, can be prepared usinga compound of Formula XIII, i.e., a6-amino-2-halo-5-alkoxy-4-substituted pyrimidine. The method of Scheme 8includes reacting a compound of Formula XIII with an oxidant to form acompound of Formula XIV.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₁represents a hydrocarbon chain; and R₃ and R₄ independently represent H,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxyl, C₁-C₆ alkoxy,amino, C₁-C₆ acyl, C₁-C₆ carboalkoxy, C₁-C₆ alkylcarbamyl, C₁-C₆alkylsulfonyl, C₁-C₆ trialkylsilyl, or C₁-C₆ dialkyl phosphonyl, or R₃and R₄ taken together with N represent a 5- or 6-membered saturatedring. The oxidant may be ozone (O₃).

The method of Scheme 8 includes contacting the hydrocarbon chain at the4 position of the pyrimidine ring of the compound of Formula XIII withan oxidant to form a carbonyl group at the 4 position of the pyrimidinering in the resulting compound of Formula XIV. Thus, the compound ofFormula XIV may be the carbaldehyde derivative of the compound ofFormula XIII.

The method of Scheme 8 may include introducing the oxidant with one ormore solvent(s). The solvent may be a halogenated solvent, e.g.,dichloromethane (DCM). The solvent may be methanol.

Accordingly, the method of Scheme 8 provides a method of using acompound of Formula XIII to prepare a compound of Formula XIV. Also, thecombined methods of Schemes 7 and 8 provide a method of using a compoundof Formula I to prepare a compound of Formula XIV. Also, the combinedmethods of Schemes 2, 7, and 8 provide a method of using a compound ofFormula III to prepare a compound of Formula XIV. Formed compounds mayor may not be isolated between combined schemes.

Another embodiment of forming a compound of Formula IX is shown inScheme 9, as follows:

As shown in Scheme 9, a compound of Formula IX, i.e., an alkyl6-amino-2-halo-5-alkoxy-pyrimidine-4-carboxylate, can be prepared usinga compound of Formula XIV, i.e., a6-amino-2-halo-5-alkoxy-pyrimidine-4-carbaldehyde.

In this case, X₁ represents a halogen; Q represents a C₁-C₂ alkoxy; R₂represents an alkyl; and R₃ and R₄ independently represent H, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, hydroxyl, C₁-C₆ alkoxy, amino,C₁-C₆ acyl, C₁-C₆ carboalkoxy, C₁-C₆ alkylcarbamyl, C₁-C₆ alkylsulfonyl,C₁-C₆ trialkylsilyl, or C₁-C₆ dialkyl phosphoryl, or R₃ and R₄ takentogether with N represent a 5- or 6-membered saturated ring.

The method of Scheme 9 includes contacting the carbonyl group at the 4position of the pyrimidine ring of the compound of Formula XIV withbromine in an alcohol of Formula VI to form a carboalkoxy group at the 4position of the pyrimidine ring in the resulting compound of Formula IX.

Accordingly, like the method of Scheme 4, the method of Scheme 9provides a method of preparing a compound of Formula IX. Also, themethod of Scheme 9 provides a method of using a compound of Formula XIVto prepare a compound of Formula IX. Also, the combined methods ofSchemes 8 and 9 provide a method of using a compound of Formula XIII toprepare a compound of Formula IX. Also, the combined methods of Schemes7 through 9 provide a method of using a compound of Formula I to preparea compound of Formula IX. Also, the combined methods of Schemes 2 and 7through 9 provide a method of using a compound of Formula III to preparea compound of Formula IX. Formed compounds may or may not be isolatedbetween combined schemes.

It is recognized that some reagents and reaction conditions disclosedherein or in the chemical literature for preparing compounds of FormulasIX, XI, XII, or derivatives thereof, may not be compatible with certainfunctionalities present in the intermediates. In these instances, theincorporation of protection/deprotection sequences or functional groupinterconversions into the synthesis will aid in obtaining the desiredproducts. The use and choice of the protection groups will be apparentto one skilled in chemical synthesis.

One skilled in the art will recognize that, in some cases, after theintroduction of a given reagent as disclosed herein or in the chemicalliterature, it may be necessary to perform additional routine syntheticsteps not described in detail to complete the synthesis of thepyrimidine compounds described above. One skilled in the art will alsorecognize that it may necessary to perform a combination of the stepsdisclosed herein or in the chemical literature in an order other thanthat implied by the particular sequence presented to prepare thepyrimidine compounds described above.

Finally, one skilled in the art will also recognize that pyrimidinecompounds described above and the intermediates thereof described hereinor in the chemical literature can be subjected to various electrophilic,nucleophilic, radical, organometallic, oxidation, and reductionreactions to add substituents or modify existing substituents.

The compounds of Formula XI have been found to be useful aspre-emergence and post-emergence herbicides. Therefore, the describedpyrimidine compounds of Formulas I, II, III, V, VII, IX, XIII, or XIV,or the agriculturally acceptable derivatives thereof, including, forexample, pyrimidine compounds of Formula XII, are useful intermediatesin the formation of herbicides prepared with compounds of Formula XI orthe like. The term herbicide is used herein to mean an active ingredientthat kills, controls, or otherwise adversely modifies the growth ofplants.

The following examples are presented to illustrate various embodimentsof the present disclosure in more detail. These examples are not to beconstrued as being exhaustive or exclusive as to the scope of thisinvention.

EXAMPLES Example 1 Preparation of 2,6-dichloro-5-methoxy-4-vinylpyrimidine

2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using2,6-dichloro-5-methoxy pyrimidine, which is commercially available. To asolution of 2,6-dicholoro-5-methoxy pyrimidine (100 g, 0.55 mol) in drytetrahydrofuran (THF) solvent was added, dropwise, 1M vinyl magnesiumbromide in THF solvent (124 g, 0.94 mol) for one hour at roomtemperature. The mixture was then stirred for 4 h at room temperature.Excess Grignard reagent was quenched by addition of acetone (200 mL)while the temperature of the mixture was maintained at a temperaturebelow 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)(151 g, 0.67 mol) was added at once and stirred overnight. A yellowsolid precipitated out. The solid was filtered and washed with ethylacetate (500 mL). The filtrate was concentrated under reduced pressureand the resulting crude compound was diluted with ethyl acetate (2 L).The resulting undissolved, dark, semi-solid was separated by filtrationusing ethyl acetate. It was further concentrated under reduced pressureto provide a crude compound, which was purified by columnchromatography. The compound was eluted with 5% to 10% ethyl acetate inhexane mixture to provide the title compound (70 g, 60% yield): mp60-61° C.; ¹H NMR (CDCl₃) δ 3.99 (s, 3H), 5.85 (d, 1H). 6.75 (d, 1H),6.95 (dd, 1H).

Example 2 Preparation of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine

2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using2,6-dichloro-5-methoxy pyrimidine, which is commercially available.2,6-Dichloro-5-methoxy pyrimidine (12.5 g, 69.8 mmol) was combined in aflask with THF (125 mL) and placed in a room temperature water bath.Vinyl magnesium bromide (78 mL, 76.8 mmol) was added in three portions.The mixture was stirred for 5 h. Acetone was added to quench anyremaining Grignard reagent. DDQ (19 g, 83.8 mmol) was added to themixture, and the mixture was stirred overnight. The mixture was thenconcentrated to remove the THF. Dichloromethane (DCM) was added,triturated, and allowed to stand over the weekend before being filtered,concentrated, and purified by column chromatography on silica gel usinga 5-30% ethyl acetate/hexane gradient. This produced the title compound(7.95 g), which was observed to be a light yellow solid that turned greyin light.

Example 3 Preparation of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine

2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using2,6-dichloro-5-methoxy pyrimidine, which is commercially available.2,6-Dichloro-5-methoxy pyrimidine (10 g, 56 mmol) was dissolved in THF(15 mL). The solution was added dropwise to vinyl magnesium bromide (60mL of 1 M, 60 mmol) over approximately 15 minutes while keeping thetemperature of the mixture below 30° C. by external cooling. Rapid,clean formation of a dihydro-vinyl pyrimidine intermediate (having amolar weight of 206 g/mol) was observed using GC-MS and HPLC. Themixture was stirred for approximately 3 h at room temperature.Conversion of greater than 95% was observed by GC/FID. The mixture wascooled to below 10° C. and treated in portions with citric acid (150 mLof 10% citric acid). It was then diluted with ethyl acetate (75 mL). Thephases were separate and the organic phase extracted using ethyl acetate(1×50 mL). The organic phases were then combined and washed withsaturated sodium chloride (1×50 mL), then dried, and evaporated toprovide a crude dihydro intermediate. This material was dissolved in DCM(200 mL) and treated with manganese dioxide (10.4 g, 120 mmol) whilestirred at room temperature. The rapid formation of2,6-dichloro-5-methoxy-4-vinyl pyrimidine (having a molar weight of 204g/mol) was observed. After about 1 h, an additional amount of manganesedioxide (15 g) was added and the mixture stirred overnight. Themanganese dioxide was removed by filtration through celite. The filtratewas washed with DCM and acetone. The filtrate was then concentrated byallowing the solvents to evaporate and purified by column chromatographyusing silica with a ramp of 0-10% ethyl acetate/hexane. This providedthe title compound (approximately 500 mg, approximately 4% yield): mp59-60° C.

Example 4 Preparation of 2,6-dichloro-5-methoxy-4-allyl pyrimidine

2,6-Dichloro-5-methoxy-6-allyl pyrimidine may be prepared using2,6-dichloro-5-methoxy pyrimidine, which is commercially available.2,6-Dichloro-5-methoxy pyrimidine (3.0 g, 17 mmol) was dissolved in THF(30 mL) and treated in portions with allyl magnesium bromide (17 mL of1M allyl magnesium bromide in diethyl ether, 17 mmol). The resultingreaction was exothermic. External cooling was used to keep thetemperature of the mixture below 30° C. After 20 minutes, the mixturewas subjected to HPLC and GC-MS. After 45 minutes, the mixture wascooled in ice/salt and the reaction quenched with saturated ammoniumchloride (30 mL) then diluted with ethyl acetate (75 mL). The organicphase was washed with saturated sodium chloride (30 mL), dried, andevaporated. The residue was dissolved in 1,4-dioxane (50 mL), treatedwith DDQ (3.9 g, 17 mmol), and stirred for 20 h. GC-MS showed presenceof 2,6-dichloro-5-methoxy-6-allyl pyrimidine (having molar weight of 218g/mol). The residue was washed in water and ethyl acetate and purifiedby column chromatography using silica with ethyl acetate and hexane.This provided the title compound (2.5 g, 67% yield): mp 61-62° C. ¹H NMR(400 MHz, CDCl₃) δ 6.07-5.94 (m, 1H), 5.26-5.16 (m, 2H), 3.94-3.89 (s,3H), 3.65-3.56 (m, 2H)); EIMS m/z 218.

Example 5 Preparation of 2,6-dichloro-5-methoxy-4-furan-2-yl pyrimidine

2,6-Dichloro-5-methoxy-4-furan-2-yl pyrimidine may be prepared using2,6-dichloro-5-methoxy pyrimidine, which is commercially available.Furan (20.4 g, 300 mmol) was dissolved in THF (44 mL) and diethyl ether(88 mL). The furan solution was cooled to about −20° C. and treated inportions with butyllithium (28 mL of 2.5 M, 70 mmol). The furan andbutyllithium solution was stirred at −15° to −5° C. for approximately 75minutes. Magnesium bromide (19 g, 74 mmol) in diethyl ether was added atabout −2° C. and stirred for 40 minutes, then cooled to −20° C. This wasthen added to 2,6-dichloro-5-methoxy pyrimidine (10.0 g, 56 mmol) andstirred at −15° C. to −20° C. for 30 minutes, then warmed to roomtemperature and stirred for 3 h. The reaction was quenched by theaddition of saturated ammonium chloride. DDQ was added, and then thesolution was stirred with 15 h. GC-MS showed near complete conversion ofthe 2,6-dichloro-5-methoxy pyrimidine (with a molar weight of 178 g/mol)to 2,6-dichloro-5-methoxy-4-furan-2-ylpyrimidine (with a molar weight of244 g/mol). The mixture was diluted by THF (150 mL) and water (100 mL).The pH of the mixture was lowered to acidic levels by the addition ofhydrochloric acid (6 M). The organic phase was separated and extractedwith an additional 100 mL of ethyl acetate. The combined organic phaseswere washed with saturated sodium chloride, dried, and concentrated ontosilica gel (50 g). The dried material was added to the top of a silicagel column and eluted with a 0% to 30% ethyl acetate/hexane until nofurther product eluted. This provided the isolated title compound (7.4g, 55% yield): mp 105-107° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.78-7.66 (d,J=1.7 Hz, 1H), 7.55-7.46 (d, J=3.6 Hz, 1H), 6.71-6.57 (m, 1H), 4.31-3.48(s, 3H). EIMS m/z 244.

Example 6 Preparation of2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde

The solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (50 g, 0.24mol) in dichloromethane:methanol (4:1, 2 L), prepared by Example 1, wascooled to −78° C. Ozone gas was bubbled through for 5 h. The reactionwas quenched with dimethyl sulfide (50 mL). The mixture was slowlywarmed to room temperature and concentrated under reduced pressure at40° C. to provide a crude material comprising the title compound (50.5g, 100% yield); HPLC (85% acetonitrile buffered with 0.1% v/v aceticacid. The title compound was not isolated from the crude material.

Example 7 Preparation of2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde

A solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (6.64 g, 32.5mmol, prepared by Example 2), in methanol:dichloromethane (1:4, 300 mL),was cooled to −78° C. in a dry ice/acetone bath. Ozone was bubbled intothe reaction until the starting material was no longer present accordingto thin layer chromatography (TLC). Dimethyl sulfide (6 mL) was added.The mixture was concentrated on a rotary evaporator at 0° C. to removethe dichloromethane. This provided an unpurified material comprising thetitle compound. The title compound was not isolated from the unpurifiedmaterial.

Example 8 Preparation of methyl2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate

A solution of 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde (seeExamples 6 and 7 above for methods for preparing this compound) (50 g,0.24 mol) in methanol (1 L) and water (60 mL) was prepared. To thesolution, sodium bicarbonate (400 g) was added. A 2 M solution ofbromine (192 g, 1.2 mol) in methanol/water (600 mL, 9:1) was added,dropwise, to the pyrimidine solution for 45 minutes at 0° C. whilestirring the mixture. The stirring was continued at the same temperaturefor 1 h. Later, the mixture was stirred at room temperature for 4 h.While stirring, the reaction mixture was thereafter poured onto amixture of crushed ice (2 L), sodium bisulfite (50 g), and sodiumchloride (200 g). The product was extracted with ethyl acetate (1 L×2),and the combined organic layer was dried over sodium sulfate andfiltered. Evaporation of the solvent under reduced pressure produced athick material, which was then solidified on long standing. Thisproduced the title compound (50.8 g, 87% yield); LC-MS 238 (m+1); HPLC(95% acetonitrile buffered with 0.1% v/v acetic acid.

Example 9 Preparation of methyl2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate

The 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde crude material(32.5 mmol), prepared by Example 7, was cooled to 0° C. in an ice/waterbath. It was assumed that approximately 60 mL of methanol was stillpresent in the crude material. Additional methanol (60 mL) and water (13mL) was added to the chilled crude material. Solid sodium bicarbonate(54.7 g) was added, and the solution stirred vigorously. A 2 M solutionof bromine (81.4 mL, 163 mmol) in methanol and water (9:1) was dropwiseadded to the crude material solution over 30 minutes. The reactingmixture was stirred at 0° C. for 1 h. The mixture was then removed fromthe ice/water bath, and the reaction monitored using GCMS. About 6 hafter initiating the reaction with bromine, a mixture of Na₂S₂O₃.5H₂O(4.5 g), saturated NaCl (150 mL), and ice (400 g) was prepared and, intothis, the reaction mixture was poured. This was diluted with ethylacetate (200 mL), and additional ethyl acetate (200 mL) was used toextract the product. The combined organic phases were dried over sodiumsulfate, filtered, and toluene (50 mL) was then added. The product wasthen concentrated on a rotary evaporator with a bath temperature of lessthan or equal to 25° C. Obtained was a yellow oil comprising the titlecompound (3.1 g, 45% yield). The title compound was not isolated fromthe solution.

Example 10 Preparation of methyl6-amino-2-chloro-5-methoxy-pyrimidine-4-carboxylate

A solution comprising the reaction mixture prepared by Example 8, whichreaction mixture contained the methyl2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (25 g, 0.1 mol), anddimethyl sulfoxide (DMSO) was prepared. To this solution was added, at0-5° C., a solution of ammonia in DMSO (2 eq). This mixture was stirredat the same 0-5° C. temperature for 10 to 15 minutes. Later, the mixturewas diluted with ethyl acetate, and the resulting solid was filtered.The filtrate was washed with a brine solution. The organic layer wasdried over sodium sulfate. Upon concentration, the crude product wasobtained. The crude product was stirred in a minimum amount of ethylacetate and filtered to obtain the pure compound. The resultingfiltrate, after concentration, was column purified. This produced thetitle compound (11 g, 50% yield): mp 158° C.; ¹H NMR (DMSO-d6) δ 3.71(s, 3H), 3.86 (s, 3H), 7.65 (brs, 1H), 8.01 (brs, 1H).

Example 11 Preparation of methyl6-amino-2-chloro-5-methoxy-pyrimidine-4-carboxylate

To a solution comprising the reaction mixture (3.1 g) prepared byExample 9, which reaction mixture contained the methyl2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (approximately 32.5mmol), was added DMSO (33 mL). This mixture was cooled to 0° C. in anice/water bath. Ammonia was bubbled through the mixture in 1 minuteintervals. The resulting reaction was followed by TLC, checking forconsumption of the starting material. The reaction mixture was dilutedwith ethyl acetate (200 mL) and then filtered. The organic phase wasthen washed with saturated sodium chloride and a 50% ethyl acetate, 50%hexane solution. Then it was back extracted with ethyl acetate (200 mL).The organic phases were combined and dried over sodium sulfate,filtered, and concentrated. Then a minimum amount of ethyl acetate wasadded before further filtering. The resulting filtrate was dripped intohexane (500 mL) and then filtered again. The resulting filtrate wasconcentrated and saved. This produced the title compound (1.38 g).

Example 12 Preparation of 6-amino-2-chloro-5-methoxy-4-furan-2-ylpyrimidine

2,6-Dichloro-5-methoxy-4-furan-2-yl pyrimidine (500 mg, 2.0 mmol) (seeExample 5 for the preparation of 2,6-dicholor-5-methoxy-4-furan-2-ylpyrimidine) was dissolved in dry DMSO (10 mL) and heated to 60° C. Thismixture was treated with a gentle stream of ammonia. After approximately2 h, conversion was complete to about a 95:5 ratio of mono-amino isomers(having a molar weight of 225 g/mol). This mixture was cooled anddiluted with water (50 mL), and the product extracted with ethyl acetate(2×50 mL). Then, the product was washed with ethyl acetate, twice withwater (25 mL), and once with saturated sodium chloride (25 mL). Theresult was dried and concentrated. The product was purified by columnchromatography using silica with a 5 to 20% ramp of ethyl acetate/hexaneto give the title compound (400 mg, 89% yield). The various isomers werenot separated.

Example 13 Preparation of 2-chloro-5-methoxy-6-vinylpyrimidin-4-amine

A solution of 2,6-dichloro-5-methoxy-6-vinyl pyrimidine (which isprepared as described in Example 2), and dimethyl sulfoxide (DMSO) isprepared. To this solution is added, at 0-5° C., a solution of ammoniain DMSO (2 eq). This mixture is stirred at the same 0-5° C. temperaturefor 10 to 15 minutes. Later, the mixture is diluted with ethyl acetate,and the resulting solid is filtered. The filtrate is washed with a brinesolution. The organic layer is dried over sodium sulfate. Uponconcentration, the crude product is obtained. The crude product isstirred in a minimum amount of ethyl acetate and filtered to obtain thepure compound. The resulting filtrate, after concentration, is columnpurified. This produces the title compound.

Example 14 Preparation of6-amino-2-chloro-5-methoxypyrimidine-4-carbaldehyde

A solution of 2-chloro-5-methoxy-6-vinylpyrimidin-4- inmethanol:dichloromethane (1:4,), is cooled to −78° C. in a dryice/acetone bath. Ozone is bubbled into the reaction until the startingmaterial is no longer present according to thin layer chromatography(TLC). Dimethyl sulfide is added. The mixture is concentrated on arotary evaporator at 0° C. to remove the dichloromethane. This providesa crude material comprising the title compound.

Example 15 Preparation of methyl6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate

A solution of 6-amino-2-chloro-5-methoxypyrimidine-4-carbaldehyde inmethanol (1 L) and water is prepared. To the solution, sodiumbicarbonate is added. A 2 M solution of bromine in methanol/water (9:1)is added, dropwise, to the pyrimidine solution for 45 minutes at 0° C.while stirring the mixture. The stirring is continued at the sametemperature for 1 h. Later, the mixture is stirred at room temperaturefor 4 h. While stirring, the reaction mixture is poured onto a mixtureof crushed ice, sodium bisulfite, and sodium chloride. The product isextracted with ethyl acetate, and the combined organic layer is driedover sodium sulfate and filtered. Evaporation of the solvent underreduced pressure produces the title compound.

While the invention may be susceptible to various modifications andalternative forms, specific embodiments have been described by way ofexample in detail herein. However, it should be understood that theinvention is not intended to be limited to the particular formsdisclosed. Rather, the invention is to cover all modifications,equivalents, and alternatives falling within the scope of the inventionas defined by the following appended claims and their legal equivalents.

What is claimed is:
 1. A compound of the formula I

wherein X₁ represents a halogen; R₁ represents a member selected fromthe group consisting of vinylic, aryl, alkenyl, and furanyl; and Qrepresents a C₁-C₂ alkoxy.
 2. The compound of claim 1 in which X₁represents chlorine.
 3. The compound of claim 1 in which Q representsmethoxy.
 4. The compound of claim 1 in which R₁ represents vinylic.
 5. Acompound of the formula II

wherein X₁ represents a halogen; and Q represents a C₁-C₂ alkoxy.
 6. Thecompound of claim 5 in which X₁ represents chlorine.
 7. The compound ofclaim 5 in which Q represents methoxy.
 8. The compound of claim 1 inwhich R₁ represents vinyl, allyl, or furanyl.